Hepatoprotection of auraptene from peels of citrus fruits against thioacetamide-induced hepatic fibrosis in mice by activating farnesoid X receptor

摘要

Hepatic fibrosis is a pathological process that eventually leads to the development of cirrhosis and liver cancer by various types of chronic liver disease. To date, there is no standard treatment for the progression of liver fibrosis. This study aims to investigate the hepatoprotection of auraptene (AUR), a simple coumarin contained in the peels of citrus fruits such as grapefruit, against thioacetamide (TAA)-induced hepatic fibrosis in mice. The involvement of farnesoid X receptor (FXR) in the anti-fibrotic effect of AUR was further elucidated using in vivo and in vitro experiments. AUR was found to remarkably protect against liver injury induced by TAA in mice and maintain the homeostasis of bile acids via the regulation of FXR-target genes including Bsep, Mrp2, Ntcp, Cyp7a1 and Cyp8b1. Masson and Sirius red staining indicated a reduction of the collagen content in the liver of AUR treated mice. Furthermore, AUR inhibited the activation of hepatic stellate cells (HSCs) by down-regulating the expression of TGF-beta 1 and a-SMA and expressed anti-inflammatory effects by reducing the expression of NF-kappa B, TNF-alpha and IL-1 beta. However, the changes in these genes and protein as well as ameliorative liver histology induced by AUR were abrogated by FXR antagonist guggulsterone in vivo and FXR siRNA in vitro. Overall, AUR protects against TAAinduced hepatic fibrosis due to the reduction of toxic bile acids and inhibition of hepatic stellate cell (HSC) activation and inflammation, which were all in association with FXR activation. AUR might be efficacious for the prevention and treatment of hepatic fibrosis in mice.